ASYMMETRIC SYNTHESIS AND ITS APPLICATIONS

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Many organic compounds of biological and chemical interest such as medicines, hormones, and vitamins are chiral, and asymmetric catalytic (AC) processes provide a highly efficient means of synthesizing enantiometrically pure substrates. This proposal is aimed mainly at the design and development of such AC processes for four fundamental organic reactions, as itemized below. Part I. The AC Aldol Reaction. Two types of AC processes will be explored. (a) It has been found recently that Sn(IV) (O-t-Bu)4 and related achiral species efficiently catalyze the Mukaiyama-type aldol reaction that involves an aldehyde and a vinyloxysilane to provide the corresponding aldol product. Sn(IV) catalysts with a chiral ligand will be examined. (b) Many boron-mediated aldol reactions proceed stereoselectively to afford the boron aldolate products. Efforts will be made to render some of these reactions catalytic by generating the boron-enolates from the boron aldolates through transesterification or transmetallation. Part II. AC Allyl- and (E)- and (Z)-Crotylmetallation. Two strategies will be explored. (a) The complex (dppeRhC1)2 has just been found to catalyze allylstannation of benzaldehyde with allytributylstannane. This exciting discovery, the first of this kind, will be followed by an extensive search for an optimum set of catalytic metal, ligand, and reagent. (b) The use of a chiral bifunctional catalyst has been highly successful in the Itsuno-Corey reduction of a ketone with diborane and Oguni-Soai-Noyori alkylation of an aldehyde with diethylzinc. This device has now been applied to allylboration with moderate success. The work should and will be continued to enhance the degree of asymmetric induction. Part III. The AC Conjugate Addition of Organometallic Reagents to the alpha,beta-unsaturated Carbonyl System. Our major efforts in this area will concern the design and synthesis of chiral ligands for (a) the cuprate and (b) zincate catalysts. In addition, (c) an exploratory search will be made to discover catalysts capable of effecting conjugate addition of relatively unreactive alkylmetals exemplified by (RO)2BR,R2Zn,R4Ge and R4Sn. Part IV. Design of Chiral Ligands for Transition Metal Catalysts Which Are Used in Hydrogenation, Ketone Reduction, and Hydrosilylation. New types of ligands have been designed to enhance the interaction between the chiral moiety and an incoming reactant and will be examined for their efficiency in the AC processes. In addition to the above AC processes, the synthesis of new chiral boron reagents of high diastereofacial selectivity is included in Part I as Part Ic. The reagents are in high demand for stereochemical control of the aldol-type assembly of two chiral fragments, a process often encountered in convergent natural product syntheses.